Recent comments in /f/askscience

lurkythere t1_ja8s5ye wrote

Reply to Is there a genetic disease where the heterozygote has more severe disease symptoms than the homozygote? by Altranite-

Yes! PCHDH19-related epilepsy only occurs in heterozygotes. Basically, neurons will express a particular type of cellular junction based on the version of PCDH19 expressed in that cell. If all neurons are mutant, it does not cause problems. But, if there are both variant and wild type neurons present, the mismatch leads to severe epilepsy. This is further complicated by the fact that PCDH19 is on the X chromosome, so males are typically hemizygous (only one copy of the gene) and therefore females are the only ones expected to be affected. This is a reversal of what we typically see in X linked disorders. Homozygous females are also not affected.

Things like Klinefelter syndrome (XXY male), mosaicism, and skewed X inactivation can add even more complexity. But again, it all comes down to whether there are more than one type of PCDH19 being expressed. The fact that males with Klinefelter can have PCDH19 related epilepsy demonstrates that this is not a sex limited disorder, but rather a heterozygote (or mosaic) limited disorder.

http://epilepsygenetics.net/the-epilepsiome/pcdh19-this-is-what-you-need-to-know/

https://www.sciencedirect.com/science/article/pii/S0887899419309269?casa_token=bpHYPTkg5HwAAAAA:DB4d1pgHBXslHmidMxFDYSxDymsUjCJ5_QGpRLIaGsL0Yt7RGZmiYqCmhzMpbnNK1M9YFa7HDkk

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jubears09 t1_ja8qpu7 wrote

Reply to Is there a genetic disease where the heterozygote has more severe disease symptoms than the homozygote? by Altranite-

Yes; the best studied mechanism for this is cellular interference.

PCDH19 is the classic human disease example. It's a protocadherin (cell surface protein that affects migration, signaling, etc) on the X chromosome. When both normal and abnormal PCDH19 is present (XX heterozygotes) affected individuals have epilepsy and developmental delay because neurons with different variants behave differently and have trouble forming networks with each other. XY males, regardless of whether there is a mutant or wt allele are normal. XXY males or mosaic males have the same phenotype as heterozygous females.

This is an illustration: https://www.ncbi.nlm.nih.gov/books/NBK98182/figure/depienne.f4/

EFNB1 is another example: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3605834/

OLD paper postulating this: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1686061/

Edit: I know you said you're not interested in sex chromosomes, but this disease mechanism applies just as easily to autosomal genes. We can predict based on males that a true mutant homozygote would be unaffected while a compound heterozygote would be affected.

The problem with finding an autosomal example is being homozygous outside of a consanguinous situation is exceedingly improbable. Not only do both alleles need to develop a disease causing mutation, but they need to mutate in the same way by chance. Most recessive diseases we see are caused by a compound heterozygous state; which while not wild type, it also not homozygous.

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North-Pea-4926 t1_ja8pz1x wrote

Reply to Is there a genetic disease where the heterozygote has more severe disease symptoms than the homozygote? by Altranite-

I can’t find examples of particular diseases, but there are situations where heterozygous individuals have lower fitness than homozygous individuals. Try searching for disruptive selection or underdominance. Or causes for low hybrid fitness.

In plants there is “hybrid necrosis” as a result of incompatible immune systems. Mammals have “hybrid sterility”.

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TestTubeRagdoll t1_ja8pmnk wrote

Reply to comment by [deleted] in Is there a genetic disease where the heterozygote has more severe disease symptoms than the homozygote? by Altranite-

> There are some disorders where the normal allele in heterozygotes confers some advantage, such as with Huntington's disease. Wexler, N. S., et al. (1987). Homozygotes for Huntington's disease. Nature, 326(6109), 194–197. https://doi.org/10.1038/326194a0

Just wanted to point out that this is a pretty outdated reference (from before the causative gene for HD was actually identified - they had a rough idea of the locus based on linkage analysis in HD families). As far as I am aware, there isn’t any strong evidence that the normal allele in heterozygotes confers an advantage in HD - and the article you linked actually states that homozygotes and heterozygotes appear to have the same phenotype, suggesting a true dominant condition, rather than one where heterozygosity is advantageous. There is a caveat that homozygotes for HD are quite rare, so studies involving them can be somewhat small.

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